Chronic renal disease (CKD) is closely related with poor cardiovascular outcomes. Our recent experimental data indicate that Na/K-ATPase reduction may be related with renal insufficiency-induced cardiac dysfunction. First, we have observed that 5/6th partial nephrectomy (PNx) induces a time-dependent decrease of Na/K-ATPase in the mouse heart along with maladaptive cardiac remodeling and deterioration in heart function. The left ventricle initially shows hypertrophic growth and then dilation, which correlates with changes in Na/K-ATPase expression. Second, we have new evidence demonstrating that reduction in Na/K-ATPase potentiates cardiotonic steroid (CTS)-induced cardiac cell death in vitro, and dilated cardiomyopathy in vivo. In transgenic mice, genetic reduction of Na/K-ATPase stimulates the expression of pro-apoptotic proteins and potentiates CTS-induced cardiac cell death. It also causes decreased contractile function in these mice. Third, our data have revealed that in normal cardiac cells there exists a self-protection mechanism preserving the membrane abundance of Na/K-ATPase and protecting cells from death. Reduction of Na/K-ATPase attenuates the signaling function that is related with this self-protection. Furthermore, our work demonstrates that endogenous CTS are elevated in animals and humans with renal diseases. These studies lead us to hypothesize that reduction of Na/K-ATPase together with a sustained increase in CTS potentiates myocyte apoptosis and results in cardiac dysfunctions in renal insufficiency. To test this hypothesis we will conduct experiments in a well established PNx animal model, and use transgenic mice and newly developed tools to assess the pathways that are related with myocyte death. In parallel, we will perform the human study to link renal function and CTS release to cardiac dysfunction.